Gliederung

Objective: Grafts of the ventral mesencephalon (VM) of E14 rat embryos, implanted into the dopamine (DA) depleted striatum (STR) of unilateral 6-hydroxydopamine (6-OHDA) adult rat model of Parkinson’s disease (PD), can restore DA neurotransmission in the transplanted area and partially reverse the motor deficits. However, these DA–rich grafts are unable to completely restore the PD phenotype, since STR DA levels are restored only up to 30% of normal. The main reason of this ectopic placement is the apparent inability of VM grafts placed in the substantia nigra (SN) to outgrow fibers to reach and reinnervate the DA denervated STR in the adult 6-OHDA model. In contrast, in the neonatal model, graft derived fibers and outgrowth can be observed until postnatal day (P) 10 when fetal VM cell suspension is transplanted into a lesioned brain. The present study was designed to investigate the influence of the age of the host on axonal outgrowth of transplanted fetal DAergic grafts implanted to the SN of the neonatal rat model of PD.

Methods: Neonatal rats were lesioned bilaterally by intraventricular injection of 6-OHDA at P1 and received VM grafts at P10, P11, P12, P13, P15 and P18 into the right SN (n=20 per group-120 000 cells per animal). Within three months from surgery the animals underwent drug-induced rotations and injections of the retrograde tracer FluroGold in the right STR to examine the possible connections between the transplanted intranigral cells and the denervated STR, followed by tyrosine hydroxylase immunohistochemistry.

Results: A significant difference (+90%) was observed in the apomorphine-induced rotation among the P11, P12 and P13 groups compared to P15 and P18. Amphetamine-induced rotation shows no difference among the experimental groups. Both rotation results were significant different between the experimental groups and the lesion controls. Morphological and stereological analysis of the graft shows a significant DA cell survival and fibre outgrowth from SN to STR in P11 (800Â±200 cells), P12 (500Â±80 cells), and P13 (200Â±50 cells), but no longer in P15 and P18.

Conclusions: In conclusion, the ability of E14 VM grafts to extend axons along the nigrostriatal pathway is determined by the development cues expressed during the early postnatal age. A better understanding of the developmental regulation of long –distance axon growth may help us to develop modified transplantation procedures which will allow better integration and long distance connectivity also in adult recipients.